Purpose Somatic deletions that affect the lymphoid transcription factor-coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1. The IKZF1 group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 ± 6% compared with 79 ± 5% in patients with IKZF1 deletion who did not fulfill the IKZF1 definition and 87 ± 1% in patients who lacked an IKZF1 deletion ( P ≤ .001). Respective 5-year cumulative relapse incidence rates were 44 ± 6%, 11 ± 4%, and 10 ± 1% ( P ≤ .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1. The IKZF1 prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1 patients was 94 ± 5% versus 40 ± 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1 patients ( P ≤ .001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% ( P ≤ .001). Conclusion IKZF1 describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1 patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP-BFM ALL 2017.
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http://dx.doi.org/10.1200/JCO.2017.74.3617 | DOI Listing |
Front Pediatr
December 2024
Laboratory of Translational Research, Children's Hospital of Brasília, Brasília, Brazil.
Introduction: There is consistent evidence that may be a driver gene in B-ALL and that selected cases may benefit from the use of FLT3 inhibitors. Our study was conducted to evaluate the frequency and types of FLT3 mutations in pediatric patients with B-ALL, the relative expression of this gene, and their influence on clinical evolution.
Methods: We evaluated 156 children with B-ALL treated between July 2018 and September 2023.
Dent Med Probl
December 2024
Department of Cancer Prevention and Therapy, Wroclaw Medical University, Poland
Background: Multiple myeloma (MM) is a hematological malignancy characterized by the presence of abnormal plasma cells. It is associated with anemia, bone lesions and renal dysfunction. Immunomodulatory drugs (IMiDs) are commonly used in MM treatment.
View Article and Find Full Text PDFJ Neuroinflammation
December 2024
Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, 08036, Barcelona, Spain.
Schizophrenia is a complex multifactorial disorder and increasing evidence suggests the involvement of immune dysregulations in its pathogenesis. We observed that IKZF1 and IKZF2, classic immune-related transcription factors (TFs), were both downregulated in patients' peripheral blood mononuclear cells (PBMCs) but not in their brain. We generated a new mutant mouse model with a reduction in Ikzf1 and Ikzf2 to study the impact of those changes.
View Article and Find Full Text PDFiScience
December 2024
Institute for Advanced Biosciences, Keio University, Yamagata 997-0017, Japan.
Lenalidomide (LEN) is commonly used as an effective therapeutic agent for multiple myeloma (MM). However, in some patients, primary resistance to LEN is observed, the mechanisms of which remain poorly understood. In this study, we combined a LEN sensitivity assay with proteomics data from 15 MM cell lines to identify protein expression profiles associated with primary LEN resistance.
View Article and Find Full Text PDFIntegr Biol (Camb)
January 2024
Department of Biotechnology, School of Bioscience and Technology (SBST), Vellore Institute of Technology (VIT), Vellore District, Tamil Nadu State, 632014, India.
Acute myeloid leukemia (AML) accounts for 1.3% of all cancers, with a limited survival of only 30%, and treating AML is a continuous challenge in medicine. IKZF1 is a DNA-binding protein that is highly mutated and undruggable but significant in causing AML.
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